The specific aim of the present project is the search for an interaction between low-dose tamoxifen and the synthetic retinoid 4-HPR on a set of surrogate endpoint biomarkers (SEBs) in premenopausal women with in situ or minimally invasive breast cancer. This will be accomplished through a double-blind placebo controlled trial with a 2x2 factorial design, whereby women will be randomized to either placebo, or tamoxifen, 10 mg/day, or 4- HPR, 200 mg/day, or both agents for two years. Since both agents inhibit second primary breast cancer incidence as well as circulating IGF-l levels in premenopausal women and because there is substantial evidence for the critical role played by this growth factor in the pathophysiology of breast cancer, the main outcome measure is the change in plasma IGF-l after two years of intervention. Another important endpoint is he change in the percentage of mammographic density as assessed by quantitative measurement. Secondary endpoints are the change in epithelial dysplasia and Ki67 obtained by ultrasound-guided fine needle aspirate of the contralateral breast add the change in endometrial thickness and proliferation as valuated by transvaginal ultrasonography and pipelle aspiration curette. Finally, assessment of toxicity of the combination regimen is an important objective of the trial. A total of 300 women should be accrued in two years to detect an interaction of 10 ng/ml in plasma IGF-l and of 4% in mammographic density after two years of intervention (power = 90%, two-tailed 5% significance). It is reasonable to assume that a synergistic interaction upon plasma IGF-l and mammographic density could result in a substantial preventive effect on breast Carcinogenesis. The validity of SEBs will be further assessed by their baseline inter-relationships and also the correlations in the changes in these SEBs within the four treatment groups. The study may thus provide essential information on the activity of the combined treatment upon breast carcinogenesis and endometrial proliferation which may lead to the implementation of a safe and successful phase 111 intervention rial aimed at reducing breast cancer incidence in a broader population of at- risk women.